Detergent-based spermicides are the most popular forms of reversible contraception in the United States the active ingredient in these spermicides is nonoxynol-9 (N-9), a non-ionic surfactant, which has been available in various forms for over 30 years. Surfactant spermicides have high contraceptive failure rate and interfere with natural and protective vaginal mechanisms thereby enhancing the risk of transmission and infection by a sexually transmitted disease. It would be desirable, therefore, to provide improved vaginal spermicides without toxicity. In a systematic search effort to identify non-toxic spermicides potentially capable of performing better and without the drawback of detergent-type spermicides, we have rationally designed and synthesized several disubstituted metallocene derivatives, where bis(cyclopentadienyl) moieties are positioned in a tetrahedral symmetry and in a bent conformation with respect to the central transition metal atoms. We discovered bis (cyclopentadienyl) complexes of vanadium(IV) or vanadocenes to have rapid, potent, and selective spermicidal activity. They work by targeting the motility-apparatus of sperm Vanadocenes lack membrane toxicity and hence have the potential to perform better, than those available today. We have synthesized a series of vanadocenes and studied how chemical modification of simple inorganic vanadium salt alters the properties of vanadium as potent spermicides. Unlike N-9, vanadocenes are spermicidal at nanomolar to micromolar ranges without cytotoxicity to human female genital tract epithelial cells and lack mucosal, systemic, and reproductive toxicity in animal models. Vanadocenes, because of their potent spermicidal activity and lack of inflammatory and toxic effects, may be useful as a new class of vaginal contraceptives for women. Results of our in vitro and in vivo studies indicated that the lead vanadocene complex, vanadocene dithiocatbamate (VDDTC), would be an attractive candidate to further explore as a vaginal spermicide. Therefore, preclinical studies will be performed to test the in vivo contraceptive efficacy in the relevant animal model. The porcine model was found to be a suitable animal model for investigating the in vivo contraceptive efficacy of spermicidal vanadocenes. Using the minipig model, we will test our hypothesis that vaginally delivered gel-microemulsion formulation of VDDTC prior to artificial insemination will prevent the conception without side effects. We will test the dose and duration of vaginally applied gel formulation of VDDTC on fertility rates in artificially inseminated and hormonally primed gilts. The development of a mechanism-based spermicide aimed at mild contraception will be a potentially paradigm shifting area in contraception research. The preclinical data on the in vivo efficacy of gel formulation of VDDTC will be essential to further explore the utility of VDDTC as an intravaginal spermicide in Phase II.